Toll-Like Receptor 4-Mediated Regulation of Spontaneous Helicobacter-Dependent Colitis in IL-10-Deficient Mice

Kabir S. Matharu; Emiko Mizoguchi; Carmen Alonso Cotoner; Deanna D. Nguyen; Bethany Mingle; Onyinye I. Iweala; Megan E. McBee; Andrew T. Stefka; Guenolee Prioult; Kevin M. Haigis; Atul K. Bhan; Scott B. Snapper; Hidehiro Murakami; David B. Schauer; Hans Christian Reinecker; Atsushi Mizoguchi; Cathryn R. Nagler

doi:10.1053/j.gastro.2009.07.004

Toll-Like Receptor 4-Mediated Regulation of Spontaneous Helicobacter-Dependent Colitis in IL-10-Deficient Mice

Kabir S. Matharu, Emiko Mizoguchi, Carmen Alonso Cotoner, Deanna D. Nguyen, Bethany Mingle, Onyinye I. Iweala, Megan E. McBee, Andrew T. Stefka, Guenolee Prioult, Kevin M. Haigis, Atul K. Bhan, Scott B. Snapper, Hidehiro Murakami, David B. Schauer, Hans Christian Reinecker, Atsushi Mizoguchi, Cathryn R. Nagler

Research output: Contribution to journal › Article › peer-review

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Abstract

Background & Aims: The commensal microbiota is believed to have an important role in regulating immune responsiveness and preventing intestinal inflammation. Intestinal microbes produce signals that regulate inflammation via Toll-like receptor (TLR) signaling, but the mechanisms of this process are poorly understood. We investigated the role of the anti-inflammatory cytokine interleukin (IL)-10 in this signaling pathway using a mouse model of colitis. Methods: Clinical, histopathologic, and functional parameters of intestinal inflammation were evaluated in TLR4^-/-, IL-10^-/-, and TLR4^-/- × IL-10^-/- mice that were free of specific pathogens and in TLR4^-/- × IL-10^-/- mice following eradication and reintroduction of Helicobacter hepaticus. Regulatory T-cell (Treg) function was evaluated by crossing each of the lines with transgenic mice that express green fluorescent protein under control of the endogenous regulatory elements of Foxp3. Apoptotic cells in the colonic lamina propria were detected by a TUNEL assay. Results: TLR4-mediated signals have 2 interrelated roles in promoting inflammation in TLR4^-/- × IL-10^-/- mice. In the absence of TLR4-mediated signals, secretion of proinflammatory and immunoregulatory cytokines is dysregulated. Tregs (Foxp3⁺) that secrete interferon-γ and IL-17 accumulate in the colonic lamina propria of TLR4^-/- × IL-10^-/- mice and do not prevent inflammation. Aberrant control of epithelial cell turnover results in the persistence of antigen-presenting cells that contain apoptotic epithelial fragments in the colonic lamina propria of Helicobacter-infected TLR4^-/- mice. Conclusions: In mice that lack both IL-10- and TLR4-mediated signals, aberrant regulatory T-cell function and dysregulated control of epithelial homeostasis combine to exacerbate intestinal inflammation.

Original language	English (US)
Pages (from-to)	1380-1390.e3
Journal	Gastroenterology
Volume	137
Issue number	4
DOIs	https://doi.org/10.1053/j.gastro.2009.07.004
State	Published - Oct 2009
Externally published	Yes

ASJC Scopus subject areas

Hepatology
Gastroenterology

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10.1053/j.gastro.2009.07.004

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Matharu, K. S., Mizoguchi, E., Cotoner, C. A., Nguyen, D. D., Mingle, B., Iweala, O. I., McBee, M. E., Stefka, A. T., Prioult, G., Haigis, K. M., Bhan, A. K., Snapper, S. B., Murakami, H., Schauer, D. B., Reinecker, H. C., Mizoguchi, A., & Nagler, C. R. (2009). Toll-Like Receptor 4-Mediated Regulation of Spontaneous Helicobacter-Dependent Colitis in IL-10-Deficient Mice. Gastroenterology, 137(4), 1380-1390.e3. https://doi.org/10.1053/j.gastro.2009.07.004

Matharu, KS, Mizoguchi, E, Cotoner, CA, Nguyen, DD, Mingle, B, Iweala, OI, McBee, ME, Stefka, AT, Prioult, G, Haigis, KM, Bhan, AK, Snapper, SB, Murakami, H, Schauer, DB, Reinecker, HC, Mizoguchi, A & Nagler, CR 2009, 'Toll-Like Receptor 4-Mediated Regulation of Spontaneous Helicobacter-Dependent Colitis in IL-10-Deficient Mice', Gastroenterology, vol. 137, no. 4, pp. 1380-1390.e3. https://doi.org/10.1053/j.gastro.2009.07.004

@article{632f6ae5d55d45a69a70cc67cf4ca18f,

title = "Toll-Like Receptor 4-Mediated Regulation of Spontaneous Helicobacter-Dependent Colitis in IL-10-Deficient Mice",

abstract = "Background & Aims: The commensal microbiota is believed to have an important role in regulating immune responsiveness and preventing intestinal inflammation. Intestinal microbes produce signals that regulate inflammation via Toll-like receptor (TLR) signaling, but the mechanisms of this process are poorly understood. We investigated the role of the anti-inflammatory cytokine interleukin (IL)-10 in this signaling pathway using a mouse model of colitis. Methods: Clinical, histopathologic, and functional parameters of intestinal inflammation were evaluated in TLR4-/-, IL-10-/-, and TLR4-/- × IL-10-/- mice that were free of specific pathogens and in TLR4-/- × IL-10-/- mice following eradication and reintroduction of Helicobacter hepaticus. Regulatory T-cell (Treg) function was evaluated by crossing each of the lines with transgenic mice that express green fluorescent protein under control of the endogenous regulatory elements of Foxp3. Apoptotic cells in the colonic lamina propria were detected by a TUNEL assay. Results: TLR4-mediated signals have 2 interrelated roles in promoting inflammation in TLR4-/- × IL-10-/- mice. In the absence of TLR4-mediated signals, secretion of proinflammatory and immunoregulatory cytokines is dysregulated. Tregs (Foxp3+) that secrete interferon-γ and IL-17 accumulate in the colonic lamina propria of TLR4-/- × IL-10-/- mice and do not prevent inflammation. Aberrant control of epithelial cell turnover results in the persistence of antigen-presenting cells that contain apoptotic epithelial fragments in the colonic lamina propria of Helicobacter-infected TLR4-/- mice. Conclusions: In mice that lack both IL-10- and TLR4-mediated signals, aberrant regulatory T-cell function and dysregulated control of epithelial homeostasis combine to exacerbate intestinal inflammation.",

author = "Matharu, {Kabir S.} and Emiko Mizoguchi and Cotoner, {Carmen Alonso} and Nguyen, {Deanna D.} and Bethany Mingle and Iweala, {Onyinye I.} and McBee, {Megan E.} and Stefka, {Andrew T.} and Guenolee Prioult and Haigis, {Kevin M.} and Bhan, {Atul K.} and Snapper, {Scott B.} and Hidehiro Murakami and Schauer, {David B.} and Reinecker, {Hans Christian} and Atsushi Mizoguchi and Nagler, {Cathryn R.}",

year = "2009",

month = oct,

doi = "10.1053/j.gastro.2009.07.004",

language = "English (US)",

volume = "137",

pages = "1380--1390.e3",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "4",

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TY - JOUR

T1 - Toll-Like Receptor 4-Mediated Regulation of Spontaneous Helicobacter-Dependent Colitis in IL-10-Deficient Mice

AU - Matharu, Kabir S.

AU - Mizoguchi, Emiko

AU - Cotoner, Carmen Alonso

AU - Nguyen, Deanna D.

AU - Mingle, Bethany

AU - Iweala, Onyinye I.

AU - McBee, Megan E.

AU - Stefka, Andrew T.

AU - Prioult, Guenolee

AU - Haigis, Kevin M.

AU - Bhan, Atul K.

AU - Snapper, Scott B.

AU - Murakami, Hidehiro

AU - Schauer, David B.

AU - Reinecker, Hans Christian

AU - Mizoguchi, Atsushi

AU - Nagler, Cathryn R.

PY - 2009/10

Y1 - 2009/10

N2 - Background & Aims: The commensal microbiota is believed to have an important role in regulating immune responsiveness and preventing intestinal inflammation. Intestinal microbes produce signals that regulate inflammation via Toll-like receptor (TLR) signaling, but the mechanisms of this process are poorly understood. We investigated the role of the anti-inflammatory cytokine interleukin (IL)-10 in this signaling pathway using a mouse model of colitis. Methods: Clinical, histopathologic, and functional parameters of intestinal inflammation were evaluated in TLR4-/-, IL-10-/-, and TLR4-/- × IL-10-/- mice that were free of specific pathogens and in TLR4-/- × IL-10-/- mice following eradication and reintroduction of Helicobacter hepaticus. Regulatory T-cell (Treg) function was evaluated by crossing each of the lines with transgenic mice that express green fluorescent protein under control of the endogenous regulatory elements of Foxp3. Apoptotic cells in the colonic lamina propria were detected by a TUNEL assay. Results: TLR4-mediated signals have 2 interrelated roles in promoting inflammation in TLR4-/- × IL-10-/- mice. In the absence of TLR4-mediated signals, secretion of proinflammatory and immunoregulatory cytokines is dysregulated. Tregs (Foxp3+) that secrete interferon-γ and IL-17 accumulate in the colonic lamina propria of TLR4-/- × IL-10-/- mice and do not prevent inflammation. Aberrant control of epithelial cell turnover results in the persistence of antigen-presenting cells that contain apoptotic epithelial fragments in the colonic lamina propria of Helicobacter-infected TLR4-/- mice. Conclusions: In mice that lack both IL-10- and TLR4-mediated signals, aberrant regulatory T-cell function and dysregulated control of epithelial homeostasis combine to exacerbate intestinal inflammation.

AB - Background & Aims: The commensal microbiota is believed to have an important role in regulating immune responsiveness and preventing intestinal inflammation. Intestinal microbes produce signals that regulate inflammation via Toll-like receptor (TLR) signaling, but the mechanisms of this process are poorly understood. We investigated the role of the anti-inflammatory cytokine interleukin (IL)-10 in this signaling pathway using a mouse model of colitis. Methods: Clinical, histopathologic, and functional parameters of intestinal inflammation were evaluated in TLR4-/-, IL-10-/-, and TLR4-/- × IL-10-/- mice that were free of specific pathogens and in TLR4-/- × IL-10-/- mice following eradication and reintroduction of Helicobacter hepaticus. Regulatory T-cell (Treg) function was evaluated by crossing each of the lines with transgenic mice that express green fluorescent protein under control of the endogenous regulatory elements of Foxp3. Apoptotic cells in the colonic lamina propria were detected by a TUNEL assay. Results: TLR4-mediated signals have 2 interrelated roles in promoting inflammation in TLR4-/- × IL-10-/- mice. In the absence of TLR4-mediated signals, secretion of proinflammatory and immunoregulatory cytokines is dysregulated. Tregs (Foxp3+) that secrete interferon-γ and IL-17 accumulate in the colonic lamina propria of TLR4-/- × IL-10-/- mice and do not prevent inflammation. Aberrant control of epithelial cell turnover results in the persistence of antigen-presenting cells that contain apoptotic epithelial fragments in the colonic lamina propria of Helicobacter-infected TLR4-/- mice. Conclusions: In mice that lack both IL-10- and TLR4-mediated signals, aberrant regulatory T-cell function and dysregulated control of epithelial homeostasis combine to exacerbate intestinal inflammation.

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Toll-Like Receptor 4-Mediated Regulation of Spontaneous Helicobacter-Dependent Colitis in IL-10-Deficient Mice

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